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1.
Mol Genet Metab ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31375398

RESUMO

OBJECTIVE: To provide recommendations for managing hypersensitivity adverse events (HAEs) to an injectable enzyme substitution therapy (pegvaliase, a PEGylated phenylalanine ammonia lyase enzyme) in adult patients with phenylketonuria (PKU). METHODS: Eight European academic immunology experts with a broad range of experience in hypersensitivity, anaphylaxis, and/or drug reactions, and two geneticists from the USA with pegvaliase experience convened for two advisory board meetings. Efficacy, safety, and immunological profile of pegvaliase were discussed with the objective of developing recommendations for the clinical management of HAEs associated with pegvaliase treatment. RESULTS: Based on available immunogenicity data, it was concluded that pegvaliase induces a Type III hypersensitivity reaction, causing HAEs with peak event rates during induction/titration and a decline over time during maintenance therapy. The decline in HAEs with longer duration of therapy was considered to likely be driven by anti-drug antibody affinity maturation, reduced immune complex formation, and decreased complement activation over time. Immunology and PKU experts unanimously supported that the use of an induction, titration, and maintenance dosing regimen and implementation of several risk mitigation strategies contributed to the improvement of tolerability over time. Key risk mitigation strategies utilized in the Phase 3 clinical trials such as premedication with H1-receptor antagonists, allowance for a longer titration period after an HAE, patient education, and requirement to carry auto-injectable adrenaline (epinephrine) should be continued in clinical practice. A tool for administration of auto-injectable adrenaline in patients using pegvaliase was suggested. It was added that after the occurrence of a severe HAE a temporary dose reduction is more likely to improve tolerability than treatment interruption. CONCLUSIONS: Overall, it was agreed that pegvaliase has a generally tolerable safety profile in adults with PKU. Importantly, the risk mitigation strategies utilized in the clinical trials were considered to support the continued use of key strategies for management in the commercial setting, such as a slow induction/titration dosing paradigm and premedication with H1-receptor antagonists. However, physicians and patients need to be aware of the risk of HAEs associated with pegvaliase; presence of a trained observer during early treatment may be beneficial in certain circumstances, and a requirement to carry auto-injectable adrenaline is recommended. Because pegvaliase offers the possibility to normalize diet, while maintaining blood phenylalanine within the recommended therapeutic range, safe use of this medication in the clinical setting is important. Ongoing monitoring of long-term clinical safety of patients on pegvaliase treatment in the commercial setting was recommended.

2.
Ther Umsch ; 75(1): 33-37, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31282835

RESUMO

The diagnosis of drug allergy is essentially based on a detailed anamnesis, involving the doctors who first treated the patient, and skin testing (prick, intradermal and epicutaneous / patch tests). In the allergological practice / clinic, provocation tests with the presumed trigger are only carried out if the indication is very clear (see articles in this issue on drug allergy children, allergies to betalactam and other antibiotics as well as analgesic intolerance). The provocation with a probably tolerable alternative is in the foreground. Unfortunately, the skin tests of certain drug groups have a low sensitivity even under optimal conditions, but very good specificity. Accordingly, positive skin tests are mostly relevant, but negative skin tests cannot rule out an allergy. In recent years, it has therefore proved successful to carry out supplementary laboratory tests in the clarification of drug allergies. The serological tests (IgE) are of little help. In contrast, the test forms based on the analysis of leukocytes (basophil activation test, BAT, and lymphocyte transformation test, LTT) have gained in importance and complement the diagnostic repertoire. In the combination of all test methods (skin test, LTT, BAT, sometimes provocation test) the trigger of a drug allergy can be defined in a good 70 % of cases and in most cases a safe therapeutic alternative can be found. In the following, we will discuss the importance of laboratory diagnostics in drug allergy.


Assuntos
Hipersensibilidade a Drogas , Testes Cutâneos , Antibacterianos , Criança , Hipersensibilidade a Drogas/diagnóstico , Humanos , Ativação Linfocitária , beta-Lactamas
3.
Int J Mol Sci ; 20(7)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974795

RESUMO

Transient receptor potential (TRP) channels have emerged as potential sensors and transducers of inflammatory pain. The aims of this study were to investigate (1) the expression of TRP channels in intervertebral disc (IVD) cells in normal and inflammatory conditions and (2) the function of Transient receptor potential ankyrin 1 (TRPA1) and Transient receptor potential vanilloid 1 (TRPV1) in IVD inflammation and matrix homeostasis. RT-qPCR was used to analyze human fetal, healthy, and degenerated IVD tissues for the gene expression of TRPA1 and TRPV1. The primary IVD cell cultures were stimulated with either interleukin-1 beta (IL-1ß) or tumor necrosis factor alpha (TNF-α) alone or in combination with TRPA1/V1 agonist allyl isothiocyanate (AITC, 3 and 10 µM), followed by analysis of calcium flux and the expression of inflammation mediators (RT-qPCR/ELISA) and matrix constituents (RT-qPCR). The matrix structure and composition in caudal motion segments from TRPA1 and TRPV1 wild-type (WT) and knock-out (KO) mice was visualized by FAST staining. Gene expression of other TRP channels (A1, C1, C3, C6, V1, V2, V4, V6, M2, M7, M8) was also tested in cytokine-treated cells. TRPA1 was expressed in fetal IVD cells, 20% of degenerated IVDs, but not in healthy mature IVDs. TRPA1 expression was not detectable in untreated cells and it increased upon cytokine treatment, while TRPV1 was expressed and concomitantly reduced. In inflamed IVD cells, 10 µM AITC activated calcium flux, induced gene expression of IL-8, and reduced disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and collagen 1A1, possibly via upregulated TRPA1. TRPA1 KO in mice was associated with signs of degeneration in the nucleus pulposus and the vertebral growth plate, whereas TRPV1 KO did not show profound changes. Cytokine treatment also affected the gene expression of TRPV2 (increase), TRPV4 (increase), and TRPC6 (decrease). TRPA1 might be expressed in developing IVD, downregulated during its maturation, and upregulated again in degenerative disc disease, participating in matrix homeostasis. However, follow-up studies with larger sample sizes are needed to fully elucidate the role of TRPA1 and other TRP channels in degenerative disc disease.


Assuntos
Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Degeneração do Disco Intervertebral/metabolismo , Disco Intervertebral/metabolismo , Núcleo Pulposo/metabolismo , Canal de Cátion TRPA1/biossíntese , Canais de Cátion TRPV/biossíntese , Animais , Sinalização do Cálcio , Matriz Extracelular/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/patologia , Camundongos , Camundongos Knockout , Núcleo Pulposo/patologia
4.
Neurourol Urodyn ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30499179

RESUMO

AIMS: Anterior lumbar interbody fusion procedures (ALIF) and total disc replacement (TDR) with anterior exposure of the lumbar spine entail a risk of a vascular injury and dysfunction of the sympathetic and parasympathetic nerves due to disturbance of the inferior and superior hypogastric plexus. While retrograde ejaculation is a known complication of the anterior spinal approach in males, post-operative sexual as well as urinary function in females has not yet been thoroughly investigated and was hence the aim of this study. METHODS: Fifteen female patients documented their sexual and urinary function preoperatively, 3 months and 6 months postoperatively, using the validated questionnaires FSFI (Female Sexual Function Index) and ICIQ (International Consultation of Incontinence Questionnaire). Randomization tests were used to statistically analyze expectation values over time (two-sided, P < 0.05). RESULTS: While no statistically significant change in the total FSFI score occurred over time, a significant increase in FSFI desire score was noted between preoperative (2.95 ± 0.8) and 6 months follow-up (3.51 ± 0.6, P = 0.02). Urinary continence remained unchanged over time. CONCLUSION: In summary, ALIF and lumbar TDR do not seem to negatively influence sexual and urinary function in females. In contrast, increased sexual desire was noted, likely secondary to post-surgical pain relief.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30334934

RESUMO

BACKGROUND: There are only a few prospective clinical trials investigating the effects of different anesthetic techniques on clinical outcomes after lumbar spine surgery. The purpose of this study was to evaluate clinical outcomes in patients receiving general (GA) and regional anesthesia (RA) for lumbar spine surgery. METHODS: This was a single-center, 2-arm, trial in which 100 patients undergoing lumbar spine surgery were randomized to receive either RA or GA (50 per group). The primary endpoint was morphine consumption during the first postoperative 48 hours. In addition, anesthesia time, transition time (defined as time from end of surgery to admission to the postoperative anesthesia care unit), visual analogue scale (VAS) for pain, and patient satisfaction at hospital discharge were recorded. RESULTS: There was no difference in the primary endpoint (cumulative morphine consumption at 48 h) between the 2 anesthesia types. Anesthesia and transition times were significantly shorter in the RA compared with the GA group-anesthesia time 125.4±23.6 minutes for GA versus 99.4±13.5 minutes for RA, transition time 22.5 minutes for GA versus 10.0 minutes for RA (both P<0.001). The VAS for pain on arrival to the postoperative anesthetic care unit was lower for patients who received RA compared with GA (crude and adjusted, both <0.001). 84% of patients in the RA group were completely satisfied compared with 74% in the GA group (P<0.001). There was a significant difference in the sex analysis for VAS for pain over time; females reported higher VAS for pain from the preoperative assessment to 6 weeks after the operation (P<0.001). CONCLUSIONS: There was no difference in postoperative morphine consumption in patients receiving GA and RA for lumbar spine surgery. RA was associated with shorter anesthesia and transition times, lower VAS for pain at arrival at the postoperative anesthesia care unit, and higher patient satisfaction at hospital discharge.

6.
Front Immunol ; 9: 1706, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30174670

RESUMO

Degenerative disc disease is associated with increased expression of pro-inflammatory cytokines in the intervertebral disc (IVD). However, it is not completely clear how inflammation arises in the IVD and which cellular compartments are involved in this process. Recently, the endoplasmic reticulum (ER) has emerged as a possible modulator of inflammation in age-related disorders. In addition, ER stress has been associated with the microenvironment of degenerated IVDs. Therefore, the aim of this study was to analyze the effects of ER stress on inflammatory responses in degenerated human IVDs and associated molecular mechanisms. Gene expression of ER stress marker GRP78 and pro-inflammatory cytokines IL-6, IL-8, IL-1ß, and TNF-α was analyzed in human surgical IVD samples (n = 51, Pfirrmann grade 2-5). The expression of GRP78 positively correlated with the degeneration grade in lumbar IVDs and IL-6, but not with IL-1ß and TNF-α. Another set of human surgical IVD samples (n = 25) was used to prepare primary cell cultures. ER stress inducer thapsigargin (Tg, 100 and 500 nM) activated gene and protein expression of IL-6 and induced phosphorylation of p38 MAPK. Both inhibition of p38 MAPK by SB203580 (10 µM) and knockdown of ER stress effector CCAAT-enhancer-binding protein homologous protein (CHOP) reduced gene and protein expression of IL-6 in Tg-treated cells. Furthermore, the effects of an inflammatory microenvironment on ER stress were tested. TNF-α (5 and 10 ng/mL) did not activate ER stress, while IL-1ß (5 and 10 ng/mL) activated gene and protein expression of GRP78, but did not influence [Ca2+]i flux and expression of CHOP, indicating that pro-inflammatory cytokines alone may not induce ER stress in vivo. This study showed that IL-6 release in the IVD can be initiated following ER stress and that ER stress mediates IL-6 release through p38 MAPK and CHOP. Therapeutic targeting of ER stress response may reduce the consequences of the harsh microenvironment in degenerated IVD.

7.
Eur Spine J ; 27(10): 2621-2630, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29968164

RESUMO

PURPOSE: Prolonged bed rest and microgravity in space cause intervertebral disc (IVD) degeneration. However, the underlying molecular mechanisms are not completely understood. Transient receptor potential canonical (TRPC) channels are implicated in mechanosensing of several tissues, but are poorly explored in IVDs. METHODS: Primary human IVD cells from surgical biopsies composed of both annulus fibrosus and nucleus pulposus (passage 1-2) were exposed to simulated microgravity and to the TRPC channel inhibitor SKF-96365 (SKF) for up to 5 days. Proliferative capacity, cell cycle distribution, senescence and TRPC channel expression were analyzed. RESULTS: Both simulated microgravity and TRPC channel antagonism reduced the proliferative capacity of IVD cells and induced senescence. While significant changes in cell cycle distributions (reduction in G1 and accumulation in G2/M) were observed upon SKF treatment, the effect was small upon 3 days of simulated microgravity. Finally, downregulation of TRPC6 was shown under simulated microgravity. CONCLUSIONS: Simulated microgravity and TRPC channel inhibition both led to reduced proliferation and increased senescence. Furthermore, simulated microgravity reduced TRPC6 expression. IVD cell senescence and mechanotransduction may hence potentially be regulated by TRPC6 expression. This study thus reveals promising targets for future studies. These slides can be retrieved under Electronic Supplementary Material.

9.
Eur Spine J ; 27(3): 564-577, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29204735

RESUMO

PURPOSE: To investigate and compare the occurrence of inflammatory processes in the sites of disc degeneration in the lumbar and cervical spine by a gene array and subsequent qPCR and to investigate the mechanistic involvement of transient receptor potential channels TRPC6 and TRPV4. METHODS: The gene expression of inflammatory cytokines and TRP channels was measured in human disc samples obtained from patients undergoing discectomy at the cervical (n = 24) or lumbar (n = 27) spine for degenerative disc disease (DDD) and disc herniation (DH) and analyzed for differences with regard to spinal level, IVD degeneration grade, Modic grade, age, sex, disc region and surgical extent. RESULTS: Aside from genes with known implication in DDD and DH, four previously unreported genes from the interferon and TRP families (IFNA1, IFNA8, IFNB1, TRPC6) could be detected. A correlation between gene expression and age (IL-15) and IVD degeneration grade (IFNA1, IL-6, IL-15, TRPC6), but not Modic grade, was identified. Significant differences were detected between cervical and lumbar discs (IL-15), nucleus and annulus (IL-6, TNF-α, TRPC6), single-level and multi-level surgery (IL-6, IL-8) as well as DDD and DH (IL-8), while sex had no effect. Multiple gene-gene pair correlations, either between different cytokines or between cytokines and TRP channels, exist in the disc. CONCLUSION: This study supports the relevance of IL-6 and IL-8 in disc diseases, but furthermore points toward a possible pathological role of IL-15 and type I interferons, as well as a mechanistic role of TRPC6. With limited differences in the inflammatory profile of cervical and lumbar discs, novel anti-inflammatory or TRP-modulatory strategies for the treatment of disc pathologies may be applicable independent of the spinal region.

10.
J Allergy Clin Immunol ; 141(2): 730-740, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28554560

RESUMO

BACKGROUND: A subgroup of patients with common variable immunodeficiency (CVID) experience immune dysregulation manifesting as autoimmunity, lymphoproliferation, and organ inflammation and thereby increasing morbidity and mortality. Therefore treatment of these complications demands a deeper comprehension of their cause and pathophysiology. OBJECTIVES: On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients. METHODS: We quantified TH1/TH2/TH17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation. RESULTS: Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3+CCR6- TH1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-γ production in peripheral CD4 memory T cells and lymph node-derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-γ production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet)+ B cells in lymph nodes, and an accumulation of T-bet+CD21low B cells in peripheral blood of affected patients. CONCLUSION: Identification of excessive IFN-γ production by blood and lymph node-derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21low B cells might serve as a marker of this IFN-γ-associated dysregulation.

12.
Rev Med Suisse ; 13(547): 261, 2017 Jan 25.
Artigo em Alemão | MEDLINE | ID: mdl-28704001
13.
Int Arch Allergy Immunol ; 172(3): 129-138, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28315874

RESUMO

Multiple drug hypersensitivity (MDH) is a syndrome that develops as a consequence of massive T-cell stimulations and is characterized by long-lasting drug hypersensitivity reactions (DHR) to different drugs. The initial symptoms are mostly severe exanthems or drug rash with eosinophilia and systemic symptoms (DRESS). Subsequent symptoms due to another drug often appear in the following weeks, overlapping with the first DHR, or months to years later after resolution of the initial presentation. The second DHR includes exanthema, erythroderma, DRESS, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hepatitis, and agranulocytosis. The eliciting drugs can be identified by positive skin or in vitro tests. The drugs involved in starting the MDH are the same as for DRESS, and they are usually given in rather high doses. Fixed drug combination therapies like sulfamethoxazole/trimethoprim or piperacillin/tazobactam are frequently involved in MDH, and 30-40% of patients with severe DHR to combination therapy show T-cell reactions to both components. The drug-induced T-cell stimulation appears to be due to the p-i mechanism. Importantly, a permanent T-cell activation characterized by PD-1+/CD38+ expression on CD4+/CD25low T cells can be found in the circulation of patients with MDH for many years. In conclusion, MDH is a drug-elicited syndrome characterized by a long-lasting hyperresponsiveness to multiple, structurally unrelated drugs with clinically diverse symptoms.


Assuntos
Hipersensibilidade a Drogas , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/imunologia , Humanos , Fatores de Risco
14.
Int Arch Allergy Immunol ; 171(3-4): 166-179, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27960170

RESUMO

Drug hypersensitivity reactions (DHR) are clinically and functionally heterogeneous. Different subclassifications based on timing of symptom appearance or type of immune mechanism have been proposed. Here, we show that the mode of action of drugs leading to immune/inflammatory cell stimulation is a further decisive factor in understanding and managing DHR. Three mechanisms can be delineated: (a) some drugs have or gain the ability to bind covalently to proteins, form new antigens, and thus elicit immune reactions to hapten-carrier complexes (allergic/immune reaction); (b) a substantial part of immune-mediated DHR is due to a typical off-target activity of drugs on immune receptors like HLA and TCR (pharmacological interaction with immune receptors, p-i reactions); such p-i reactions are linked to severe DHR; and (c) symptoms of DHR can also appear if the drug stimulates or inhibits receptors or enzymes of inflammatory cells (pseudo-allergy). These three distinct ways of stimulations of immune or inflammatory cells differ substantially in clinical manifestations, time of appearance, dose dependence, predictability, and cross-reactivity, and thus need to be differentiated.


Assuntos
Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/etiologia , Alérgenos/imunologia , Alérgenos/metabolismo , Reações Cruzadas/imunologia , Suscetibilidade a Doenças , Hipersensibilidade a Drogas/metabolismo , Haptenos/imunologia , Humanos , Fenótipo , Ligação Proteica , Receptores Imunológicos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo
15.
Eur Spine J ; 23(9): 1878-91, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24997157

RESUMO

PURPOSE: Although inflammatory processes play an essential role in painful intervertebral disc (IVD) degeneration, the underlying regulatory mechanisms are not well understood. This study was designed to investigate the expression, regulation and importance of specific toll-like receptors (TLRs)--which have been shown to play an essential role e.g. in osteoarthritis--during degenerative disc disease. METHODS: The expression of TLRs in human IVDs was measured in isolated cells as well as in normal or degenerated IVD tissue. The role of IL-1ß or TNF-α in regulating TLRs (expression/activation) as well as in regulating activity of down-stream pathways (NF-κB) and expression of inflammation-related genes (IL-6, IL-8, HSP60, HSP70, HMGB1) was analyzed. RESULTS: Expression of TLR1/2/3/4/5/6/9/10 was detected in isolated human IVD cells, with TLR1/2/4/6 being dependent on the degree of IVD degeneration. Stimulation with IL-1ß or TNF-α moderately increased TLR1/TLR4 mRNA expression (TNF-α only), and strongly increased TLR2 mRNA expression (IL-1ß/TNF-α), with the latter being confirmed on the protein level. Stimulation with IL-1ß, TNF-α or Pam3CSK4 (a TLR2-ligand) stimulated IL-6 and IL-8, which was inhibited by a TLR2 neutralizing antibody for Pam3CSK4; IL-1ß and TNF-α caused NF-κB activation. HSP60, HSP70 and HMGB1 did not increase IL-6 or IL-8 and were not regulated by IL-1ß/TNF-α. CONCLUSION: We provide evidence that several TLRs are expressed in human IVD cells, with TLR2 possibly playing the most crucial role. As TLRs mediate catabolic and inflammatory processes, increased levels of TLRs may lead to aggravated disc degeneration, chronic inflammation and pain development. Especially with the identification of more endogenous TLR ligands, targeting these receptors may hold therapeutic promise.


Assuntos
Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/imunologia , Disco Intervertebral/imunologia , Disco Intervertebral/fisiologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Células Cultivadas , Chaperonina 60/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Proteína HMGB1/genética , Proteínas de Choque Térmico HSP70/genética , Humanos , Mediadores da Inflamação/farmacologia , Interleucina-1beta/farmacologia , Interleucina-6/genética , Interleucina-8/genética , Disco Intervertebral/citologia , Degeneração do Disco Intervertebral/patologia , Lipopeptídeos/farmacologia , Proteínas Mitocondriais/genética , NF-kappa B/genética , Osteoartrite/imunologia , Osteoartrite/patologia , Osteoartrite/fisiopatologia , Fator de Necrose Tumoral alfa/farmacologia
16.
Eur Spine J ; 23(10): 2114-26, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24947182

RESUMO

PURPOSE: The Swiss Federal Office of Public Health demanded a nationwide HTA registry for lumbar total disc arthroplasty (TDA), to decide about its reimbursement. The goal of the SWISS spine registry is to generate evidence about the safety and efficiency of lumbar TDA. METHODS: Two hundred forty-eight cases treated between 3-2005 and 6-2006, who were eligible for the 5-year follow-up were included in the study. Follow-up rates for 3-6 months, 1, 2 and 5 years were 85.9, 77.0, 44.0 and 51.2 %, respectively. Outcome measures were back and leg pain, medication consumption, quality of life, intraoperative and postoperative complication and revision rates. Additionally, segmental mobility, ossification, adjacent and distant segment degeneration were analysed at the 5-year follow-up. RESULTS: There was a significant, clinically relevant and lasting reduction of back (preop/postop 73/29 VAS points) and leg pain (preop/postop VAS 55/22) and a consequently decreased analgesics consumption and quality of life improvement (preop/postop 0.30/0.76 EQ-5D score points) until 5 years after surgery. The rates for intraoperative and early postoperative complications were 4.4 and 3.2 %, respectively. The overall complication rate during five postoperative years was 23.4 %, and the adjacent segment degeneration rate was 10.7 %. In 4.4 % of patients, a revision surgery was performed. Cumulative survivorship probability for a revision/re-intervention-free 5-year postoperative course was 90.4 %. At the 5-year follow-up, the average range of motion of the mobile segments (86.8 %) was 9.7°. In 43.9 % of patients, osteophytes at least potentially affecting the range of motion were seen. CONCLUSIONS: Lumbar TDA appeared as efficient in long-term pain alleviation, consequent reduction of pain medication consumption and improvement of quality of life. The procedure also appeared sufficiently safe, but surgeons have to be aware of a list of potential adverse events. The outcome is stable over the 5-year postoperative period. The vast majority of treated segments remained mobile after 5 years, although almost half of patients showed osteophytes.


Assuntos
Degeneração do Disco Intervertebral/cirurgia , Disco Intervertebral/cirurgia , Dor Lombar/cirurgia , Vértebras Lombares/cirurgia , Substituição Total de Disco/métodos , Adulto , Idoso , Feminino , Seguimentos , Humanos , Prótese Articular , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados (Cuidados de Saúde) , Medição da Dor , Complicações Pós-Operatórias/cirurgia , Complicações Pós-Operatórias/terapia , Qualidade de Vida , Amplitude de Movimento Articular , Sistema de Registros/estatística & dados numéricos , Reoperação , Resultado do Tratamento , Adulto Jovem
17.
Allergo J Int ; 23(7): 261-268, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-26120536

RESUMO

Knowing the clinical warning signs of immunodeficiency (ID) in adulthood is crucial for early detection of the over 200 forms of primary ID known to date. Many of these congenital diseases with a genetic background already manifest in childhood. Antibody deficiency diseases represent an important exception, with common variable immunodeficiency (CVID) being the most common form of ID. The median age of onset of CVID is 24 years. Unfortunately, the delay in diagnosis is still in excess of 4 years. General practitioners as well as allergists play a particularly important role in early detection. ID patients who present primarily with signs of immune dysregulation pose an even greater diagnostic challenge. Thus, autoimmune cytopenia, inflammatory bowel diseases, or sarcoid-like granulomatous inflammation can be the first manifestation in up to 20 % of ID patients. Secondary forms of ID [e. g., due to long-term corticosteroid treatment, HIV-infection, leukemia, lymphoma, nephrotic syndrome, malabsorption syndrome] need to be differentiated from primary antibody deficiency. Considering the overlap with allergic symptoms [ID accompanied by a susceptibility to eczema, elevated total IgE, blood eosinophilia], the present article discusses, the clinical warning signs of ID, the first diagnostic steps required and the option of further diagnostic work up at specialist centers for complex cases, as well as the treatment options for such cases.

18.
Acta Neurochir (Wien) ; 155(10): 1923-30, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23748926

RESUMO

BACKGROUND: The objective of this study was to correlate various radiological parameters with clinical outcome in patients who had undergone lumbar total disc replacement (TDR). Lumbar TDR is one possible treatment option in patients with low back pain (LBP), offering an alternative to lumbar fusion. Favourable clinical outcome hinges on a number of radiological parameters, such as mobility, sintering, and-most importantly-accurate positioning of the implant. METHODS: A total of 46 patients received a prosthetic disc because of degenerative lumbar disc disorders. Follow-up evaluation included analysis of radiographs and subjective rating of the clinical status by the patient using the North American Spine Society (NASS) patient questionnaire, visual analogue scale (VAS) for pain and state of health, and the EuroQol EQ-5D. Radiological follow-up took place after 2 years. Coronal and sagittal positions of the prosthesis, intervertebral disc height, facet joint pressure, mobility, sintering, and calcification were evaluated. Optimal positioning of the prosthesis was defined as a central coronal position and a most dorsal position in the sagittal plane. Based on the radiologically determined placement of the prosthesis, the patient population was divided into three groups, i.e., prosthesis ideally placed (<2 mm), discretely shifted (2-3 mm), or suboptimally placed (>3 mm). RESULTS: Overall, 81 % of patients stated that they would undergo the operation again. Health status was stable at a VAS score of 7.04 points 2 years after TDR, compared to 3.97 points before TDR. Mean working capacity had increased from 53 % preoperatively to 88 % 2 years after TDR. Overall, 39 % of the prostheses were rated as ideally positioned, while 13 % were discretely shifted and 48 % were suboptimally placed with respect to one of the radiological criteria. In 80.4 % of patients, follow-up assessment after ≥2 years indicated good mobility at the operated segment, while calcification was noted in 4 % and sintering was detected in 15 % of the implants. CONCLUSIONS: Our data indicate poor correlation between clinical outcome and position of the prosthesis. Although 48 % of the implants were suboptimally placed in either the coronal or sagittal plane, most of the patients reached a very good clinical outcome. However, suboptimally placed devices appeared to cause significantly more neurological symptoms in long-term follow-up.


Assuntos
Degeneração do Disco Intervertebral/cirurgia , Dor Lombar/cirurgia , Vértebras Lombares/cirurgia , Região Lombossacral/cirurgia , Substituição Total de Disco/métodos , Adolescente , Adulto , Feminino , Humanos , Degeneração do Disco Intervertebral/complicações , Degeneração do Disco Intervertebral/patologia , Dor Lombar/diagnóstico por imagem , Dor Lombar/etiologia , Vértebras Lombares/diagnóstico por imagem , Região Lombossacral/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Medição da Dor , Radiografia , Substituição Total de Disco/efeitos adversos , Resultado do Tratamento , Adulto Jovem
19.
Eur Spine J ; 22(8): 1723-30, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23584163

RESUMO

BACKGROUND: The Swiss Federal Office of Public Health demanded a nationwide HTA-registry for cervical total disc arthroplasty (TDA), to decide about its reimbursement. The goal of the SWISSspine registry is to generate evidence about the safety and efficiency of cervical TDA. MATERIALS AND METHODS: Three hundred thirty-two cases treated between 3.2005 and 6.2006 who were eligible for 5 years follow-ups were included in the study. Follow-up rates for 3-6 months, 1, 2 and 5 years were 84.6, 74.4, 50.6 and 64.8 %, respectively. Outcome measures were neck and arm pain, medication, quality of life, intraoperative and postoperative complication and revision rates. In addition, segmental mobility, ossification, adjacent and distant segment degeneration were analyzed at the 5-year follow-up. RESULTS: There was significant, clinically relevant and lasting reduction of neck (preop/postop 60/21 VAS points) and arm pain (preop/postop VAS 67/17) and a consequently decreased analgesics consumption and quality of life improvement (preop/postop 0.39/0.82 EQ-5D points) until the 5-year follow-up. The rates for intraoperative and early postoperative complications were 0.6 and 7.2 %, respectively. In 0.6 % an early and in 3.9 % a late revision surgery was performed. At the 5-year follow-up, the average range of motion of the mobile segments (88.2 %) was 10.2°. In 40.7 % of the patients osteophytes at least potentially affecting range of motion were seen. CONCLUSIONS: Cervical TDA appeared as safe and efficient in long-term pain alleviation, consequent reduction of pain killer consumption and in improvement of quality of life. The improvement is stable over the 5 years postoperative period. The vast majority of treated segments remained mobile after 5 years, although 40.7 % of patients showed osteophytes.


Assuntos
Vértebras Cervicais/cirurgia , Degeneração do Disco Intervertebral/cirurgia , Prótese Articular , Sistema de Registros , Substituição Total de Disco/instrumentação , Adulto , Idoso , Feminino , Seguimentos , Humanos , Incidência , Degeneração do Disco Intervertebral/complicações , Degeneração do Disco Intervertebral/epidemiologia , Masculino , Pessoa de Meia-Idade , Cervicalgia/epidemiologia , Cervicalgia/etiologia , Avaliação de Resultados (Cuidados de Saúde) , Qualidade de Vida , Estudos Retrospectivos , Suíça/epidemiologia , Substituição Total de Disco/métodos , Resultado do Tratamento
20.
J Inflamm (Lond) ; 9(1): 29, 2012 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-22909087

RESUMO

BACKGROUND: As proinflammatory cytokines seem to play a role in discogenic back pain, substances exhibiting anti-inflammatory effects on intervertebral disc cells may be used as minimal-invasive therapeutics for intradiscal/epidural injection. The purpose of this study was to investigate the anti-inflammatory and anti-catabolic potential of curcuma, which has been used in the Indian Ayurvedic medicine to treat multiple ailments for a long time. METHODS: Human disc cells were treated with IL-1ß to induce an inflammatory/catabolic cascade. Different extracts of curcuma as well as curcumin (= a component selected based on results with curcuma extracts and HPLC/MS analysis) were tested for their ability to reduce mRNA expression of proinflammatory cytokines and matrix degrading enzymes after 6 hours (real-time RT-PCR), followed by analysis of typical inflammatory signaling mechanisms such as NF-κB (Western Blot, Transcription Factor Assay), MAP kinases (Western Blot) and Toll-like receptors (real-time RT-PCR). Quantitative data was statistically analyzed using a Mann Whitney U test with a significance level of p < 0.05 (two-tailed). RESULTS: Results indicate that the curcuma DMSO extract significantly reduced levels of IL-6, MMP1, MMP3 and MMP13. The DMSO-soluble component curcumin, whose occurrence within the DMSO extract was verified by HPLC/MS, reduced levels of IL-1ß, IL-6, IL-8, MMP1, MMP3 and MMP13 and both caused an up-regulation of TNF-α. Pathway analysis indicated that curcumin did not show involvement of NF-κB, but down-regulated TLR2 expression and inhibited the MAP kinase JNK while activating p38 and ERK. CONCLUSIONS: Based on its anti-inflammatory and anti-catabolic effects, intradiscal injection of curcumin may be an attractive treatment alternative. However, whether the anti-inflammatory properties in vitro lead to analgesia in vivo will need to be confirmed in an appropriate animal model.

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